Dry eye is a disease which starts with unpleasant levels of symptoms of dryness of eyes and an uncomfortable feeling in eyes and greatly prevents people from performing daily activities when the disease is worsened. The number of dry eye patients is increasing yearly in association with the coming of an aging society and the increase in VDT (video display terminal) works with personal computers. It is believed that the estimated number of dry eye patients is greater than or equal to 10,000,000 in the United States and greater than or equal to 8,000,000 in Japan.
Although the clinical conditions of dry eye are not elucidated completely, it is considered that the decrease in the volume of tear on the corneal and the conjunctival, which is caused by the decrease in the secretion of tear, the acceleration of the evaporation of tear and the like, is the main pathogenesis of dry eye. That is, the dryness of the corneal and the conjunctival associated with the decrease in the volume of tear induces pathological symptoms and/or observations including an ocular discomfort, a feeling of dryness of eyes, a feeling of fatigue of eyes, hyperemia, and keratoconjunctival epithelial disorders. If these symptoms and/or observations progress, the abnormality in vision occurs ultimately. Therefore, it is quite important to treat dry eye properly at an early stage.
It is believed that the most desired matter for the treatment methods for dry eye is to promote the secretion of tear in a dry eye patient. However, no agent for treatment of dry eye having such an activity is known. Then, in the conventional dry eye treatment, the administration of an artificial tear solution ophthalmic solution, the suppression of the excretion of tear with a punctal plug or the like is generally selected.
As an agent for treatment of dry eye, an ophthalmic solution containing hyaluronic acid has been generally used. Although hyaluronic acid does not have a tear secretion promotion action, it is disclosed in Cornea, 12(5), 433-436 (1993) (NPL 1) that, when hyaluronic acid retains multiple water molecules thereof, the hyaluronic acid can exhibit an excellent water-retaining property. Although there are various theories about the mechanism of action of an ophthalmic solution containing hyaluronic acid for the treatment of dry eye, it is believed that the water-retaining property of hyaluronic acid can alleviate the drying of the cornea and the conjunctiva.
On the other hand, a P2Y2 receptor is one of subtypes of a P2Y receptor that is a purine receptor and is believed to be deeply involved in the regulation of the secretion of a chloride ion or the like. A ligand for a P2Y receptor is considered as being a nucleotide in a living body, and it is described in Current Medicinal Chemistry, 13(3), 289-312 (2006) (NPL 2) that nucleotides typified by uridine-5′-triphosphate (UTP), adenosine-5′-triphosphate (ATP) and derivatives thereof, dinucleotides typified by P1,P4-bis(5′-uridyl)tetraphosphate (also called “diquafosol” or “INS-365”) and the like can act as agonists for a P2Y2 receptor.
In recent years, it was found that these P2Y2 receptor agonists have an action of promoting the secretion of tear, and these P2Y2 receptor agonists are drawing attention as novel agents for treatment of dry eye. For example, Current Eye Research, 21(4), 782-787 (2000) (NPL 3) discloses that UTP and ATP can promote the secretion of tear in rabbits, and therefore it is suggested that the secretion of tear can be promoted by stimulating a P2Y2 receptor. In Cornea, 23(8), 784-792 (2004) (NPL 4), it is reported that an ophthalmic solution containing diquafosol promoted the secretion of tear and ameliorated keratoconjunctival epithelial disorders in clinical tests.
However, there are still some severe dry eye patients who cannot be treated satisfactorily with the above-mentioned agents for treatment of dry eye, and therefore the development of an agent for treatment of dry eye having a more potent tear secretion promotion action has been demanded.
In Japanese National Patent Publication No. 2001-504858 (PTL 1), it is suggested that hyaluronic acid can be added as an additive to a tear secretion promoter containing a compound capable of activating a purine receptor (P2Y2 receptor). However, as mentioned in Dictionary of pharmaceutical additives, 220 (2007) (NPL 5), the largest amount of hyaluronic acid that can be used as an additive in an ophthalmic agent is 0.2 mg/g (0.02% (w/w)), and it is not described or suggested that a therapeutically effective concentration (no less than 0.1% (w/v) in terms of the concentration in an ophthalmic solution) of hyaluronic acid and a P2Y2 receptor agonist are administered in combination.
As stated above, it is not found clearly as to what effect can be achieved when a P2Y2 receptor agonist and a therapeutically effective concentration of hyaluronic acid are used in combination.